The present invention is concerned with novel quinazolinone derivatives, the preparation thereof, pharmaceutical compositions comprising said novel compounds and the use of these compounds as a medicine as well as methods of treatment by administering said compounds.
Genetic research has led to the identification of a variety of gene families in which mutations can lead to the development of a wide variety of tumors. A particular group of genes, known as ras, have been identified in mammals, birds, insects, mollusks, plants, fungi and yeasts. The family of mammalian ras genes consists of three major members (xe2x80x9cisoformsxe2x80x9d): H-ras, K-ras and N-ras genes. These ras genes code for highly related proteins generically known as p21ras. These p21ras proteins comprise a family of proteins that regulate cell growth when bound to the inner surface of the plasma membrane. However, overproduction of p21ras proteins, or mutations of said ras genes thereby coding for mutant or oncogenic forms of p21ras proteins, lead to uncontrolled cell division. In order to regulate cell growth, the ras proteins need to be attached to the inner leaflet of the plasma membranes. If mutated or oncogenic forms of p21ras, the p21ras as oncoproteins, become attached to plasma membranes, they provide a signal for the transformation of normal cells to tumor cells and promote their uncontrolled growth. To acquire this transforming potential, the precursor of the p21ras oncoprotein must undergo an enzymatically catalyzed farnesylation of the cysteine residue located in a carboxyl-terminal tetrapeptide. Therefore, inhibitors of the enzyme that catalyzes this modification, farnesyl protein transferase, will prevent the membrane attachment of p21ras and block the aberrant growth of ras-transformed tumors. Hence, it is generally accepted in the art that farnesyl transferase inhibitors can be very useful as anticancer agents for tumors in which ras contributes to transformation.
Since mutated or oncogenic forms of ras are frequently found in many human cancers, most notably in more than 50% of colon and pancreatic carcinomas (Kohl et al., Science, vol 260, 1834-1837, 1993), it has been suggested that farnesyl transferase inhibitors can be very useful against these types of cancer.
EP-0,371,564 discloses (1H-azol-1-ylmethyl) substituted quinoline, quinazoline and quinoxaline derivatives which suppress the plasma elimination of retinoic acids. Some of these compounds also have the ability to inhibit the formation of androgens from progestines and/or inhibit the action of the aromatase enzyme complex.
It has been found that the present novel compounds, all having a phenyl substituent on the 4-position of the 2-quinazolinone-moiety bearing a carbon or nitrogen-linked imidazolyl moiety, show faesyl protein transferase inhibiting activity.
The present invention concerns compounds of formula 
the pharmaceutically acceptable acid addition salts and the stereochemically isomeric forms thereof, wherein
the dotted line represents an optional bond;
X is oxygen or sulfur;
R1 and R2 each independently are hydrogen, hydroxy, halo, cyano, C1-6alkyl, trihalomethyl, trihalomethoxy, C2-6alkenyl, C1-6alkyloxy, hydroxyC1-6alkyloxy, C1-6alkyloxyC1-6alkyloxy, C1-6alkyloxycarbonyl, aminoC1-6alkyloxy, mono- or di(C1-6alkyl)aminoC1-6alkyloxy, Ar1, Ar1C1-6alkyl, Ar1oxy or Ar1C1-6alkyloxy;
R3 and R4 each independently are hydrogen, halo, cyano, C1-6alkyl, C1-6alkyloxy, Ar1oxy, C1-6alkylthio, di(C1-6alkyl)amino, trihalomethyl or trihalomethoxy;
R5 is hydrogen, halo, C1-6alkyl, cyano, haloC1-6alkyl, hydroxyC1-6alkyl, cyanoC1-6alkyl, aminoC1-6alkyl, C1-6alkyloxyC1-6alkyl, C1-6alkylthioC1-6alkyl, aminocarbonylC1-6alkyl, C1-6alkyloxycarbonylC1-6alkyl, C1-6alkylcarbonyl-C1-6alkyl, C1-6alkyloxycarbonyl, mono- or di(C1-6alkyl)aminoC1-6alkyl, Ar1, Ar1C1-6alkyloxyC1-6alkyl; or a radical of formula
xe2x80x94Oxe2x80x94R10xe2x80x83xe2x80x83(a-1),
xe2x80x94Sxe2x80x94R10xe2x80x83xe2x80x83(a-2),
xe2x80x94Nxe2x80x94R11R12xe2x80x83xe2x80x83(a-3),
xe2x80x83wherein
R10 is hydrogen, C1-6alkyl, C1-6alkylcarbonyl, Ar1, Ar1C1-6alkyl, C1-6alkyloxycarbonylC1-6alkyl, or a radical of formula -Alk-OR13 or -Alk-NR14R15;
R11 is hydrogen, C1-6alkyl, Ar1 or Ar1C1-6alkyl;
R12 is hydrogen, C1-6alkyl, C1-6alkylcarbonyl, C1-6alkyloxycarbonyl, C1-6alkylaminocarbonyl, Ar1, Ar1C1-6alkyl, C1-6alkylcarbonyl-C1-6alkyl, Ar1carbonyl, Ar1C1-6alkylcarbonyl, aminocarbonylcarbonyl, C1-6alkyloxyC1-6alkylcarbonyl, hydroxyl, C1-6alkyloxy, aminocarbonyl, di(C1-6alkyl)aminoC1-6alkylcarbonyl, amino, C1-6alkylamino, C1-6alkylcarbonylamino, or a radical or formula -Alk-OR13 or -Alk-NR14R15;
wherein Alk is C1-6alkanediyl;
R13 is hydrogen, C1-6alkyl, C1-6alkylcarbonyl, hydroxyC1-6alkyl, Ar1 or Ar1C1-6alkyl;
R14 is hydrogen, C1-6alkyl, Ar1 or Ar1C1-6alkyl;
R15 is hydrogen, C1-6alkyl, C1-6alkylcarbonyl, Ar1 or Ar1C1-6alkyl;
R6 is a radical of formula 
xe2x80x83wherein
R16 is hydrogen, halo, Ar1, C1-6alkyl, hydroxyC1-6alkyl, C1-6alkyloxyC1-6alkyl, C1-6alkyloxy, C1-6alkylthio, amino, C1-6alkyloxycarbonyl, C1-6alkylthioC1-6alkyl, C1-6alkylS(O)C1-6alkyl or C1-6alkylS(O)2C1-6alkyl;
R17 is hydrogen, C1-6alkyl or di(C1-4alkyl)aminosulfonyl;
R7 is hydrogen or C1-6alkyl provided that the dotted line does not represent a bond;
R8 is hydrogen, C1-6alkyl or Ar2CH2 or Het1CH2;
R9 is hydrogen, C1-6alkyl, C1-6alkyloxy or halo; or
R8 R9 taken together to form a bivalent radical of formula
xe2x80x94CHxe2x95x90CHxe2x80x94xe2x80x83xe2x80x83(c-1),
xe2x80x94CH2xe2x80x94CH2xe2x80x94xe2x80x83xe2x80x83(c-2),
xe2x80x94CH2xe2x80x94CH2xe2x80x94CH2xe2x80x94xe2x80x83xe2x80x83(c-3),
xe2x80x94CH2xe2x80x94Oxe2x80x94xe2x80x83xe2x80x83(c-4),
or
xe2x80x94CH2xe2x80x94CH2xe2x80x94Oxe2x80x94xe2x80x83xe2x80x83(c-5);
Arl is phenyl; or phenyl substituted with 1 or 2 substituents each independently selected from halo, C1-6alkyl, C1-6alkyloxy or trifluoromethyl;
Ar2 is phenyl; or phenyl substituted with 1 or 2 substituents each independently selected from halo, C1-6alkyl, C1-6alkyloxy or trifluoromethyl; and
Het1 is pyridinyl; pyridinyl substituted with 1 or 2 substituents each independently selected from halo, C1-balkyl, C1-6alkyloxy or trifluoromethyl.
As used in the foregoing definitions and hereinafter, halo is generic to fluoro, chloro, bromo and iodo; C1-2alkyl defines methyl or ethyl; C1-4alkyl includes C1-2alkyl and the higher homologues thereof having 3 to 4 carbon atoms such as e.g. propyl, butyl, 1-methylethyl, 2-methylpropyl and the like; C1-6alkyl includes C1-4alkyl and the higher homologues thereof having 5 to 6 carbon atoms such as, for example, pentyl, 2-methyl-butyl, hexyl, 2-methylpentyl and the like; C2-6alkenyl defines straight and branched chain hydrocarbon radicals containing one double bond and having from 2 to 6 carbon atoms such as, for example, ethenyl, 2-propenyl, 3-butenyl, 2-pentenyl, 3-pentenyl, 3-methyl-2-butenyl, and the like; C1-6alkanediyl defines bivalent straight and branched chained saturated hydrocarbon radicals having from 1 to 6 carbon atoms, such as, for example, methylene, 1,2-ethanediyl, 1,3-propanediyl, 1,4butanediyl, 1,5-pentanediyl, 1,6-hexane-diyl and the branched isomers thereof. The term xe2x80x9cS(O)xe2x80x9d refers to a sulfoxide and xe2x80x9cS(O)2xe2x80x9dto a sulfon.
The pharmaceutically acceptable acid addition salts as mentioned hereinabove are meant to comprise the therapeutically active non-toxic acid addition salt forms which the compounds of formula (I) are able to form. The compounds of formula (I) which have basic properties can be converted in their pharmaceutically acceptable acid acid addition salts by treating said base form with an appropriate acid. Appropriate acids comprise, for example, inorganic acids such as hydrohalic acids, e.g. hydrochloric or hydrobromic acid; sulfuric; nitric; phosphoric and the like acids; or organic acids such as, for example, acetic, propanoic, hydroxyacetic, lactic, pyruvic, oxalic, malonic, succinic (ie. butane-dioic acid), maleic, fumaric, malic, tartaric, citric, methanesulfonic, ethanesulfonic, benzenesulfonic, p-toluenesulfonic, cyclamic, salicylic, p-amino-salicylic, pamoic and the like acids.
The term acid addition salts also comprises the hydrates and the solvent addition forms which the compounds of formula (I) are able to form. Examples of such forms are e.g. hydrates, alcoholates and the like.
The term stereochemically isomeric forms of compounds of formula (I), as used hereinbefore, defines all possible compounds made up of the same atoms bonded by the same sequence of bonds but having different three-dimensional structures which are not interchangeable, which the compounds of formula (I) may possess. Unless otherwise mentioned or indicated, the chemical designation of a compound encompasses the mixture of all possible stereochemically isomeric forms which said compound may possess. Said mixture may contain all diastereomers and/or enantiomers of the basic molecular structure of said compound. All stereochemically isomeric forms of the compounds of formula (I) both in pure form or in admixture with each other are intended to be embraced within the scope of the present invention.
Some of the compounds of formula (I) may also exist in their tautomeric forms. Such forms although not explicitly indicated in the above formula are intended to be included within the scope of the present invention.
In those compounds where the dotted line does not represent a bond, the nitrogen on the 3-position of the quinazolinone moiety allows for an extra bond, i.e. radical R7. In those compounds where the dotted line represents a bond, said radical R7 is absent.
Wherever R8 and R9 are taken together to form a bivalent radical of formula (c-4) or (c-5), the CH2 moiety in said bivalent radical is preferably connected to the nitrogen atom of the 2-quinazolinone moiety of the compounds of formula (I).
Whenever used hereinafter, the term xe2x80x9ccompounds of formula (I)xe2x80x9d is meant to include also the pharmaceutically acceptable acid addition salts and all stereoisomeric forms.
A group of interesting compounds consists of those compounds of formula (I) wherein one or more of the following restrictions apply:
a) R1 and R2 are each independently selected from hydrogen, halo, C1-6alkyl, C1-6alkyloxy or trihalomethyl; in particular hydrogen, halo or C1-4alkyl;
b) R3 and R4 are each independently selected from hydrogen, halo, C1-6alkyl, C1-6alkyloxy or trihalomethyl; in particular hydrogen, halo or C1-4alkyl;
c) R5 is is hydrogen, hydroxy, haloC1-6alkyl, hydroxyC1-6alkyl, cyanoC1-6alkyl, C1-6alkyloxycarbonylC1-6alkyl, or a radical of formula xe2x80x94NR11R12 wherein R11 is hydrogen or C1-6alkyl and R12 is hydrogen, C1-6alkyl, C1-6alkyloxy, C1-6alkyloxy-C1-6alkylcarbonyl; in particular R5 is hydrogen, hydroxy, halo or amino;
d) R6 is a radical of formula (b-1) or (b-2) wherein R16 is hydrogen or C1-6alkyl and R17 is C1-6alkyl;
e) R7 is hydrogen or C1-6alkyl in case the dotted line does not represent a bond;
f) R8 is hydrogen, C1-6alkyl or Het1CH2;
g) R9 is hydrogen.
A particular group of compounds consists of those compounds of formula (I) wherein X is oxygen, R1 and R2 are each independently selected from hydrogen, halo or C1-4alkyl; R3 and R4 are each independently selected from hydrogen, halo or C1-4alkyl; R5 is hydrogen, hydroxy, halo or a amino; R6 is a radical of formula (b-1) or (b-2) wherein R16 is hydrogen or C1-4alkyl and R17 is C1-4alkyl; R7 is hydrogen or C1-4alkyl in case the dotted line does not represent a bond; R8 is hydrogen; C1-4alkyl or Het1CH2; and R9 is hydrogen.
Preferred compounds are those compounds of formula (I) wherein X is oxygen, R1 is 3-chloro, R2 is hydrogen, R3 is 4chloro, R4 is hydrogen, R5 is hydrogen, C1-2alkyl, halo or amino; R6 is a radical of formula (b-1) or (b-2) wherein R16 is hydrogen and R17 is C1-2alkyl; and R7 is hydrogen or C1-2alkyl in case the dotted line does not represent a bond; R8 is hydrogen; C1-2alkyl or Het1CH2; and R9 is hydrogen.
The most preferred compounds of formula (I) are
6-[amino(4-chlorophenyl)(1-methyl-1H-imidazol-5-yl)methyl]-4-(3-chlorophenyl)-1-methyl-2(1H)-quinazolinone; and
6-[amino(4-chlorophenyl)(1-methyl-1H-imidazol-5-yl)methyl]-4-(3-chlorophenyl)-3,4-dihydro-1,3-dimethyl-2(1H)-quinazolinone; the stereoisomeric forms and the pharmaceutically acceptable acid addition salts thereof.
The compounds of formula (I) wherein R6 is a radical of formula (b-1), represented by compounds of formula (I-a), can generally be prepared by N-alkylating an intermediate of formula (III), with an intermediate of formula (II), wherein W is an appropriate leaving group such as, for example, chloro, bromo, methanesulfonyloxy or benzenesulfonyloxy. The reaction can be performed in a reaction-inert solvent such as, for example, acetonitrile, and optionally in the presence of a suitable base such as, for example, sodium carbonate, potassium carbonate or triethylamine. Stirring may enhance the rate of the reaction. The reaction may conveniently be carried out at a temperature ranging between room temperature and reflux temperature. 
Also, compounds of formula (I-a) can be prepared by reacting an intermediate of formula (IV) with an intermediate of formula (V), wherein Y is carbon or sulfur, such as, for example, a 1,1xe2x80x2-carbonyldiimidazole. 
Said reaction may conveniently be conducted in a reaction-inert solvent, such as, e.g. tetrahydrofuran, optionally in the presence of a base, such as sodium hydride, and at a temperature ranging between room temperature and the reflux temperature of the reaction mixture.
The compounds of formula (I) wherein R6 represents a radical of formula (b-2), R5 is hydroxy and R17 is C1-6alkyl, said compounds being referred to as compounds of formula (I-b-1) may be prepared by reacting an intermediate ketone of formula (VI) with an intermediate of formula (III-1). Said reaction requires the presence of a suitable strong base, such as, for example, butyl lithium in an appropriate solvent, such as, for example, tetrahydrofuran, and the presence of an appropriate silanederivative, such as, for example, triethylchlorosilane. During the work-up procedure an intermediate silane derivative is hydrolyzed. Other procedures with protective groups analogous to silanederivatives can also be applied. 
Also the compounds of formula (I), wherein R6 is a radical of formula (b-2), R5 is hydroxy and R17 is hydrogen, said compounds being referred to as compounds of formula (I-b-2) may be prepared by reacting an intermediate ketone of formula (VI) with a intermediate of formula (III-2), wherein PG is a protective group such as, for example, a sulfonyl group, e.g. a dimethylamino sulfonyl group, which can be removed after the addition reaction. Said reaction is conducted analogously as for the preparation of compounds of formula (I-b-1), followed by removal of the protecting group PG, yielding compounds of formula (I-b-2).
Compounds of formula (I-c), defined as compounds of formula (I) wherein R7 is hydrogen and the dotted line does not represent a bond, can be converted into compounds of formula (I-d), defined as compounds of formula (I) wherein the dotted line represents a bond, by art-known oxidation procedures such as, e.g. oxidation with MnO2 in a reaction-inert solvent, e.g. dichloromethane. 
Conversely, compounds of formula (I-d) can be converted to compounds of formula (I-c) using art-known reduction procedures such as, e.g. treatment with sodiumborohydride in a suitable solvent, e.g. methanol.
Also, compounds of formula (I-c) can be converted to compounds of formula (I-c-1) by treating compounds (I-c) with a reagent of formula R7xe2x80x94W1, wherein W1 is an appropriate leaving group such as, for example, chloro, bromo, methanesulfonyloxy or benzenesulfonyloxy, using the above-described N-alkylation procedure. 
The compounds of formula (I-b) can be converted to compounds of formula (I-e), defined as a compound of formula (I) wherein R6 is a radical of formula (b-2) and R5 is hydrogen, by submitting the compounds of formula (I-b) to appropriate reducing conditions, such as, eg. stirring in acetic acid in the presence of formamide. 
Further, compounds of formula (I-b) can be converted to compounds of formula (I-f) wherein R5 is halo, by reacting the compounds of formula (I-b) with a suitable halogenating agent, such as, e.g. thionyl chloride or phosphorus tribromide. Successively, the compounds of formula (I-f) can be treated with a reagent of formula Hxe2x80x94NR11R12 in a reaction-inert solvent, thereby yielding compounds of formula (I-g). 
A compound of formula (I-i), defined as a compound of formula (I) wherein X is sulfur, may be prepared by reacting the corresponding compound of formula (I-h), defined as a compound of formula (I) wherein X is oxygen, with a reagent like phosphorus pentasulfide or Lawesson""s reagent in a suitable solvent such as, for example, pyridine. 
An intermediate of formula (II-a), being an intermediate formula (II) wherein X is oxygen and R7 and R8 are hydrogen, can be prepared starting from an intermediate of formula (VII). Said intermediate (VII), wherein n is 2 or 3, is conveniently prepared by protecting the corresponding art-known ketone as a ketal. An intermediate of formula (VII) is reacted with an intermediate of formula (VIII) in the presence of a base such as sodium hydroxide, in an appropriate solvent, e.g. methanol. The thus obtained intermediate of formula (IX) undergoes ring opening of the isoxazole moiety by hydrogenation of intermediate (IX) in the presence of a suitable catalyst such as, e.g. Raney Nickel. Subsequent acylation with a reactive carboxylic acid derivative, e.g. trichloroacetyl chloride or trifluoroacetyl chloride, yields an intermediate of formula (X), which undergoes ring closure in the presence of an ammonium salt, e.g. ammonium acetate, and an appropriate base such as, e.g. hexamethylphosphorous triamide (HMPT). Intermediates of formula (X) are submitted to acidic conditions and subsequently treated with art-known reducing agents such as, e.g. sodium borohydride, yielding intermediates of formula (XII). The hydroxy group of intermediates of formula (XII) is converted to a leaving group W by treating intermediates (XII) with a suitable reagent such as, e.g. methanesulfonyloxy chloride, or a halogenating reagent such as, e.g. POCl3 or SOCl2, yielding intermediates of formula (II-a). 
Intermediates of formula (II-b), defined as intermediates of formula (II) wherein X is O and R7 is hydrogen, can be prepared by reacting intermediates of formula (XI) with R8xe2x80x94W1, wherein W1 is a suitable leaving group such as, e.g. chloro, bromo, methanesulfonyloxy or benzenesulfonyloxy; using the above-described N-alkylation procedure. Subsequent reduction with e.g. sodiumborohydride in a suitable solvent, e.g. methanol, and hydrolysis under acidic conditions, yields intermediates of formula (XIV). Convertion of the hydroxy group of intermediates (XIV) into leaving group W, e.g. by treatment with methanesulfonyloxy chloride or a halogenating reagent such as, e.g. SOCl2, POCl3, gives intermediates of formula (II-b). 
Intermediates of formula (VI-a), defined as intermediates of formula (VI) wherein X is O and the dotted line does not represent a bond, can be prepared by submitting intermediates of formula (XIII) to art-known reduction procedures, such as, e.g. treatment with sodium borohydride in a reaction-inert solvent e.g. methanol, thereby yielding intermediates of formula (XV). Intermediates (XV) are N-alkylated with R7xe2x80x94W1, wherein W1 is a leaving group as above-described, and subsequently hydrolysed under acidic conditions to intermediates of formula (VI-a). 
Also, intermediates of formula (VI-b), defined as intermediates of formula (VI) wherein X is O and the dotted line represents a bond, can be prepared by hydrolysis of the intermediate of formula (IX) with an acid, such as for example, TiCl3, in the presence of water. Subsequent acylation with a reactive carboxylic acid derivative, such as, e.g. trichloroacetyl chloride, yields an intermediate of formula (XVII), which undergoes ring closure in the presence of an ammonium salt, e.g. ammonium acetate, and an appropriate base such as, e.g. hexamethylphosphorous triamide (HMPT), thereby yielding an intermediate of formula (VI-b). 
The compounds of formula (I) and some of the intermediates have at least one stereogenic center in their structure. This stereogenic center may be present in a R or a S configuration.
The compounds of formula (I) as prepared in the hereinabove described processes are generally racemic mixtures of enantiomers which can be separated from one another following art-known resolution procedures. The racemic compounds of formula (I) may be converted into the corresponding diastereomeric salt forms by reaction with a suitable chiral acid. Said diastereomeric salt forms are subsequently separated, for example, by selective or fractional crystallization and the enantiomers are liberated therefrom by alkali. An alternative manner of separating the enantiomeric forms of the compounds of formula (I) involves liquid chromatography using a chiral stationary phase. Said pure stereochemically isomeric forms may also be derived from the corresponding pure stereochemically isomeric forms of the appropriate starting materials, provided that the reaction occurs stereospecifically. Specific stereoisomers can be synthesized by stereospecific methods of preparation. These methods will advantageously employ enantiomerically pure starting materials.
This invention provides a method for inhibiting the abnormal growth of cells, including transformed cells, by administering an effective amount of a compound of the invention. Abnormal growth of cells refers to cell growth independent of normal regulatory mechanisms (e.g. loss of contact inhibition). This includes the abnormal growth of: (1) tumor cells (tumors) expressing an activated ras oncogene; (2) tumor cells in which the ras protein is activated as a result of oncogenic mutation of another gene; (3) benign and malignant cells of other proliferative diseases in which aberrant ras activation occurs. Furthermore, it has been suggested in literature that ras oncogenes not only contribute to the growth of of tumors in vivo by a direct effect on tumor cell growth but also indirectly, i.e. by facilitating tumor-induced angiogenesis (Rak. J. et al, Cancer Research, 55, 4575-4580, 1995). Hence, pharmacologically targetting mutant ras oncogenes could conceivably suppress solid tumor growth in vivo, in part, by inhibiting tumor-induced angiogenesis.
This invention also provides a method for inhibiting tumor growth by administering an effective amount of a compound of the present invention, to a subject, e.g. a mammal (and more particularly a human) in need of such treatment. In particular, this invention provides a method for inhibiting the growth of tumors expressing an activated ras oncogene by the administration of an effective amount of the compounds of the present invention. Examples of tumors which may be inhibited, but are not limited to, lung cancer (e.g. adenocarcinoma), pancreatic cancers (e.g. pancreatic carcinoma such as, for example exocrine pancreatic carcinoma), colon cancers (e.g. colorectal carcinomas, such as, for example, colon adenocarcinoma and colon adenoma), hematopoietic tumors of lymphoid lineage (e.g. acute lymphocytic leukemia, B-cell lymphoma, Burkitt""s lymphoma), myeloid leukemias (for example, acute myelogenous leukemia (AML)), thyroid follicular cancer, myelodysplastic syndrome (MDS), tumors of mesenchymal origin (e.g. fibrosarcomas and rhabdomyosarcomas), melanomas, teratocarcinomas, neuroblastomas, gliomas, benign tumor of the skin (e.g. keratoacanthomas), breast carcinoma, kidney carninoma, ovary carcinoma, bladder carcinoma and epidermal carcinoma.
This invention may also provide a method for inhibiting proliferative diseases, both benign and malignant, wherein ras proteins are aberrantly activated as a result of oncogenic mutation in genes, i.e. the ras gene itself is not activated by mutation to an oncogenic form, with said inhibition being accomplished by the administration of an effective amount of the compounds described herein, to a subject in need of such a treatment. For example, the benign proliferative disorder neurofibromatosis, or tumors in which ras is activated due to mutation or overexpression of tyrosine kinase oncogenes may be inhibited by the compounds of this invention.
Hence, the present invention discloses the compounds of formula (I) for use as a medicine as well as the use of these compounds of formula (I) for the manufacture of a medicament for treating one or more of the above mentioned conditions.
In view of their useful pharmacological properties, the subject compounds may be formulated into various pharmaceutical forms for administration purposes.
To prepare the pharmaceutical compositions of this invention, an effective amount of a particular compound, in base or acid addition salt form, as the active ingredient is combined in intimate admixture with a pharmaceutically acceptable carrier, which carrier may take a wide variety of forms depending on the form of preparation desired for administration. These pharmaceutical compositions are desirably in unitary dosage form suitable, preferably, for administration orally, rectally, percutaneously, or by parenteral injection. For example, in preparing the compositions in oral dosage form, any of the usual pharmaceutical media may be employed, such as, for example, water, glycols, oils, alcohols and the like in the case of oral liquid preparations such as suspensions, syrups, elixirs and solutions; or solid carriers such as starches, sugars, kaolin, lubricants, binders, disintegrating agents and the like in the case of powders, pills, capsules and tablets. Because of their ease in administration, tablets and capsules represent the most advantageous oral dosage unit form, in which case solid pharmaceutical carriers are obviously employed. For parenteral compositions, the carrier will usually comprise sterile water, at least in large part, though other ingredients, to aid solubility for example, may be included. Injectable solutions, for example, may be prepared in which the carrier comprises saline solution, glucose solution or a mixture of saline and glucose solution. Injectable suspensions may also be prepared in which case appropriate liquid carriers, suspending agents and the like may be employed. In the compositions suitable for percutaneous administration, the carrier optionally comprises a penetration enhancing agent and/or a suitable wetting agent, optionally combined with suitable additives of any nature in minor proportions, which additives do not cause a significant deleterious effect to the skin. Said additives may facilitate the administration to the skin and/or may be helpful for preparing the desired compositions. These compositions may be administered in various ways, e.g., as a transdermal patch, as a spot-on, as an ointment. It is especially advantageous to formulate the aforementioned pharmaceutical compositions in dosage unit form for ease of administration and uniformity of dosage. Dosage unit form as used in the specification and claims herein refers to physically discrete units suitable as unitary dosages, each unit containing a predetermined quantity of active ingredient calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier. Examples of such dosage unit forms are tablets (including scored or coated tablets), capsules, pills, powder packets, wafers, injectable solutions or suspensions, teaspoonfuls, tablespoonfuls and the like, and segregated multiples thereof.
Those skilled in the art could easily determine the effective amount from the test results presented hereinafter. In general it is contemplated that an effective amount would be from 0.01 mg/kg to 100 mg/kg body weight, and in particular from 0.05 mg/kg to 10 mg/kg body weight. It may be appropriate to administer the required dose as two, three, four or more sub-doses at appropriate intervals throughout the day. Said sub-doses may be formulated as unit dosage forms, for example, containing 0.05 to 500 mg, and in particular 0.1 mg to 200 mg of active ingredient per unit dosage form.